pressure waves as external energy to push them deep into tumor
tissues. This approach achieved especially promising results in
glioblastoma, because the blood-brain barrier is particularly hard
to overcome for drugs. A couple of years ago, researchers used
ultrasound to track therapeutic bacteria in vivo. Mikhail Shapiro
and colleagues at Caltech genetically engineered bacteria to express
what they termed acoustic reporter genes (ARG), which encode
the components of hollow structures called gas vesicles that scatter
ultrasound waves, generating an echo that enabled them to detect
the bacteria’s location deep inside living mice.^9
Other common sources of external energy that can be safely and
remotely applied in the human body are magnetic fields. While mag-
netic resonance imaging systems have been used clinically for decades,
the development of systems for magnetic guidance and control are
still fairly new. So far, researchers have applied the approach to guide
magnetic catheters for high-precision surgery. The most renowned
example is the NIOBE system from St. Louis–based Stereotaxis for
the treatment of cardiac arrhythmias. A magnetic catheter tip is pre-
cisely steered along abnormal heart tissue, where electrical pulses heat
or cool the device to ablate misfiring cells.
The use of similar magnetic instrumentation to guide bacteria
in the context of cancer therapy has been proposed by groups that
work with magnetotatic bacteria—marine microbes that naturally
synthesize strings of iron oxide nanoparticles wrapped in a lipid
shell. This trait has evolved to help them navigate in the water
by sensing the Earth’s magnetic field, with these strings working
as compass needles inside their unicellular bodies. This was first
discovered in the 1970s by Richard Blakemore of Woods Hole
Oceanographic Institution in Massachusetts. Roughly 40 years
later, Sylvain Martel of Polytechnique Montréal’s NanoRobotics
Laboratory and colleagues coupled these magnetotactic bacteria
to DOXIL, the liposome-wrapped chemotherapeutic that earned
the title of the first approved nanomedicine. Martel’s group, too,
took advantage of the fact that anaerobic bacteria tend to home
to tumors for their low-oxygen environment, and coupled that
natural homing mechanism with an external directing magnetic
field, demonstrating increased accumulation and penetration of
the therapy in mouse tumors.^10 In another recent study, one of us
(S.S.), with researchers at MIT and ETH Zurich, showed in tis-
sue models on a chip that applying rotating magnetic fields could
drive swarms of such magnetotactic bacteria to act as little pro-
pellers, creating strong flows to push companion nanomedicines
out of blood vessels and deeper into tissues.^11
While the use of such magnetotactic species inside the human
body might occur decades in the future, encoding magneto-
sensation in other, more clinically translatable or already-tested
bacterial strains might be an achievable goal in the near term.
Several of the proteins involved in the complex biomineralization
process that forms the magnetic compounds in magneto-
tactic bacteria have been identified,^12 and in a preprint pub-
lished earlier this year, researchers reported engineering E. coli
to form magnetite particles and controlling them by external
magnetic fields.^13
Another route to making non-magnetic bacteria controllable
by magnetic fields is to simply attach magnetic materials to them.
Researchers have taken one or even multiple bacterial strains and
bound them to magnetic micro- or nanoparticles. When exposed
to an external magnetic field, these magnetic particles will orient
with the field, and so will the bacteria, which will then travel in that
direction. In 2017, Metin Sitti and colleagues at the Max Planck
Institute for Intelligent Systems in Stuttgart, Germany, attached
E. coli bacteria to microparticles made of layers of the chemo-
therapeutic doxorubicin and tiny magnetic nanoparticles. Using
cancer cells in a dish, the researchers showed that they could
remotely control these drug-carrying bacterial bots with magnets
to improve tumor cell targeting compared with just adding drug-
loaded microparticles to the cells.^14
No matter how, genetically engineered bacteria empowered
by external energy sources providing triggers, control, and guid-
ance are a fascinating new direction in this field. Fueled by the
convergence of synthetic biology, mechanical engineering, and
robotics, these new approaches might just bring us one step
closer to the fantastic vision of tiny robots that seek and destroy
many cancer types. gSimone Schuerle is an assistant professor at ETH Zurich and a member
of the university’s Institute for Translational Medicine. Tal Danino is an
assistant professor at Columbia University and a member of the Herbert
Irving Comprehensive Cancer Center and the Data Science Institute.References- S. Wilhelm et al., “Analysis of nanoparticle delivery to tumours,” Nat Rev Mat,
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